Various cell encapsulation devices have been disclosed over the years. The devices are often used to provide therapeutical substances to a recipient or as bioreactors. These devices commonly comprise one of two forms: microencapsulation devices or macroencapsulation devices.
In a microencapsulation device, small quantities of cells are usually suspended in a droplet and enclosed in a semi-permeable membrane. The semi-permeable membrane allows nutrients, waste products, and therapeutic agents, for example, to diffuse across the membrane, while preventing cells and antibodies, for example, from migrating across the membrane. In order to provide enough cells to effect the desired result, microencapsulation devices are usually used in large numbers.
One common limitation of microencapsulation devices is instability of the microcapsule membrane once implanted in a recipient or placed in a bioreactor. Such instability often leads to cell death or inconsistent release of therapeutic agents. As a result, more than one administration of the microcapsules may be required.
A further limitation with many such devices is the possibility of an immunogenic reaction by a recipient to the composition used to make the semi-permeable membrane of the device. This can lead to serious illness in a recipient and/or damage to the device.
Still another limitation is the difficulty of retrieving the microcapsules from either a recipient or a bioreactor.
Representative examples of microencapsulation devices include, but are not limited to, U.S. Pat. Nos. 5,182,111, 5,283,187, and 5,389,535, all issued to Aebischer et al., U.S. Pat. Nos. 4,487,758, 4,673,566, 4,689,293, 4,806,355, and 4,897,758, each issued to Goosen et al., U.S. Pat. No. 4,803,168, issued to Jarvis, Jr., U.S. Pat. Nos. 4,352,883 and 4,391,909, both issued to Lim, U.S. Pat. No. 4,298,002, issued to Ronel et al., and U.S. Pat. No. 4,353,888, issued to Sefton.
In a macroencapsulation device, larger numbers of cells are enclosed in a chamber of some type. These devices have at least one semi-permeable membrane to allow the necessary flow of fluids while safely retaining the cells. Representative examples of macroencapsulation devices include, but are not limited to, U.S. Pat. No. 5,262,055, issued to Bae et al., U.S. Pat. No. 4,911,717, issued to Gaskill, III, U.S. Pat. No. 4,298,002, issued to Ronel et al., U.S. Pat. No. 5,387,237, issued to Fournier et al., PCT/AU90/00281, filed by Baxter International, Inc., U.S. Pat. No. 5,413,471, issued to Brauker et al., U.S. Pat. No. 5,344,454, issued to Clarke et al., U.S. Pat. No. 5,002,661, issued to Chick et al., and PCT/US94/07190, filed by W.L. Gore & Associates, Inc.
Of particular interest is the macroencapsulation device disclosed in PCT/US94/07190, filed by W.L. Gore & Associates, Inc., which is incorporated herein by reference (hereinafter "Gore device"). The Gore device is preferably a cell encapsulation device that is generally cylindrical in geometry with a flexible cell-displacing core enclosed in a selectively permeable membrane. The selectively permeable membrane contains cells within the device while permitting exchange of biochemical substances between the encapsulated cells and the exterior surface of the device. In a situation where the cell encapsulation device is embedded in a recipient and contains allogeneic or xenogeneic cells, the selectively permeable membrane also serves to isolate the encapsulated cells from the immune system of the recipient. The selective permeability of the membrane can be adjusted by impregnating the membrane with an appropriate hydrogel material. The cell displacing core positions the encapsulated cells near the selectively permeable membrane. In this way, the core positions the encapsulated cells in the device at a distance from a nutrient source and at a cell density that minimizes the diffusion distance biochemical substances must traverse between each encapsulated cell and the external environment of the device. This configuration enables a maximum number of encapsulated cells to be maintained in a given volume at high levels of viability and productivity. During assembly of the device, cells are introduced into the device as a suspension through an open end of the device. The open end is then sealed.
In the biotechnology and pharmaceutical industries, for example, there is a need to quickly and easily screen putative therapeutic agents produced by cells for toxicity, bioactivity, and efficacy, and other factors. Conventional techniques for screening therapeutic agents produced by cells include culturing the cells in vitro until sufficient quantities of cells are obtained to produce enough of the therapeutic agent for screening. Once the desired population of cells is established, the cells are allowed to secrete their products into the culture medium until sufficient amounts of the therapeutic agent are produced. The culture medium containing the putative therapeutic agent is then separated from the cells and concentrated, if necessary. The putative therapeutic agent is usually purified from the culture medium before screening. The purified agent is then screened in vitro and/or in vivo. This is often a laborious, expensive, and time consuming process.
A device and method that eliminates some of the steps of conventional screening techniques would be useful. Though the Gore device, supra, is particularly suited for this type of screening, further improvements are believed possible in the device.
One method to eliminate some steps in screening putative therapeutic agents would be to implant a cell encapsulation device of the present invention, containing cells that produce the putative therapeutic agent, into a test subject.
Once the cell encapsulation device is implanted in a test subject, the putative therapeutic agent would be delivered to the subject directly, eliminating the need to separate the cells from a culture medium and to concentrate, purify, and deliver the agent. Various assays for the putative agent could be performed on the test subject or on samples taken from the subject in order to evaluate the therapeutic agent.
In the field of gene therapy, for example, one method to effect a desired therapy is to harvest certain cells from a patient or donor and genetically manipulate the cells ex vivo to express a desired gene product. The gene product is often a substance needed by the patient, but not produced, or improperly produced, by the patient's own cells. Once the cells have been genetically engineered to produce the desired gene product, the cells are introduced directly into the patient with the intent that the cells will survive in the patient and produce the gene product in amounts and for a length of time sufficient to correct or ameliorate the gene product deficiency in the patient. Since the genetically engineered cells are introduced directly into the patient, the cells are essentially free to move and migrate throughout the patient's body. This is a serious concern because the genetically engineered cells are often transformed and contain oncogenes. The presence of such motile transformed cells in a patient often presents an unacceptable safety risk to the patient.
An implantable cell encapsulation device that prevents genetically engineered cells from contacting a patient's cells and migrating through the patient's tissues while delivering a therapeutic gene product to the patient from the encapsulated cells would be useful in the field of gene therapy.